The present invention relates to a series of novel glycerol derivatives containing a heterocyclic system and provides processes for producing these compounds and compositions containing them for therapeutic use, especially for use as antagonists to platelet activating factor (hereinafter abbreviated, as is conventional, to "PAF").
Natural PAF, at least as isolated from mammalian tissues, is a mixture of from 2 to 5 phospholipids, the number depending upon the nature of the original tissue. The major constituents of PAF may be represented by the formula (A): ##STR1## in which R represents a long chain aliphatic hydrocarbon group which may be saturated or unsaturated. Natural PAF is levorotatory and the various components of natural PAF may be identified, for example as: 1-C.sub.16:0 =formula (A) where R represents a hexadecyl group; 1-C.sub.18:0 =formula (A) where R represents an octadecyl group; 1-C.sub.18:1 =formula (A) where R represents a 9(Z)-octadecenyl group.
PAF exhibits a strong platelet activating and aggregating effect. It also has a hypotensive effect and increases vasopermeability; it is believed to be an active agent in the induction of the shock state (for example endotoxin-induced shock) and to act as a mediator of inflammatory disease. Accordingly, PAF antagonists have been investigated with a view to developing new types of anti-shock agent and of anti-inflammatory agent. Accordingly, analogs of natural PAF's have been investigated in an attempt to find such PAF antagonists. Currently, several compounds are known as PAF antagonists. For example, the compound of formula (B): ##STR2## (also known as CV-3988) is disclosed in U.S. Pat. No. 4,408,052, whilst the compound of formula (C); ##STR3## known as ONO-6240) is disclosed in European Patent Publication No. 146258. These compounds, however, are unsatisfactory for one or more of the following reasons: they lack sufficient intensity of antagonism towards PAF; the duration of their effect is insufficient; biological utilization is inadequate.
Other glycerol derivatives known to have PAF inhibitory activity are disclosed in EP Patent Publication No. 157,609, which discloses a series of glycerol derivatives for use as PAF inhibitors. Certain of the compounds disclosed therein have certain structural similarities to the compounds of the invention, although those compounds are said in that EP Specification not to be the preferred compounds. Those compounds of the EP Specification differ from the compounds of the present invention in that, where they have a heterocyclic group at the 2-position, they lack an intervening oxygen atom, which is an essential requirement of the compounds of the present invention.
We have now discovered a series of PAF antagonists which are glycerol derivatives containing a heterocyclic structure. The compounds of the present invention have been found to be excellent PAF antagonists, resulting in anti-asthmatic, anti-inflammatory and anti-shock activities which have excellent duration, bioavailability and level of activity.